CAPA (Corrective and Preventive Actions) is usually divided into three elements. If we have identified a problem with a cleaning process (which could be a process deviation or an analytical non-conformance), the parts of CAPA are:
We will explore these different (but related) elements using examples to illustrate how they differ and how they can be used. First, while I said that CAPA can be used either for process deviations or analytical non-conformances, the first step in an analytical non-conformance might be an OOS (Out of Specification) evaluation to see if there were any analytical testing (or sampling issues) that led to the nonconforming value. If an analytical or sampling error were found, then CAPA principles could be used to correct the analytical process. However, this does not necessarily mean that there was not a cleaning process deviation. There may have been a cleaning process deviation that (in addition to the analytical error) contributed to the nonconforming value. However, I can’t clearly say whether or not there was a deviation in the cleaning process unless I do a further investigation into how the cleaning was actually performed. [As a side note, it is possible that even if all analytical values were acceptable, I still might have had a cleaning process deviation. This might happen in situations where I have designed and validated a very robust cleaning process; the cleaning process deviation might have been minor so as to not cause unacceptable analytical results. However, this situation may lead to process drift, which may eventually result in failing analytical values. However, the relevant point is that you can only address known deviations.]
So, we now move to the issue of CAPA applied to the cleaning process itself. If there is an identified deviation in the cleaning process, the first step is to do a thorough investigation and apply a “Correction”. For the cleaning process, “Correction” means doing something to the equipment so it can safely be used for manufacture of the next product. There are really two situations to discuss. The first is when I have identified a deviation either during the cleaning process itself or after completion of the cleaning process but before manufacture of the next product. In these situations I should do something to make sure the equipment is clean enough so that another product can be made in that equipment. The investigation may suggest what might be a possible “Correction”. For example, the correction might be as simple as repeating the validated cleaning process, with additional supervision to make sure process deviations do not occur. At the end of that additional process, the equipment should be sampled much as was done in the original validation. If I have made a correction and verified that the residue limits were being met, then the equipment can be released (by QA) for manufacture of another product.
The second situation is more complex. In this situation, a cleaning process deviation has only been discovered after another product has been made in the cleaned equipment. In this situation, the investigation should also include a determination as to whether a subsequently manufactured product was contaminated or adulterated as a result of the cleaning process deviation. This may involve analyzing that second product for residues that might have been transferred from the equipment to the second product. This may require additional analytical studies to determine that the target residue can be suitably analyzed in the matrix of that second product. In addition, the relevant limit in this case is an L1 value (the limit in the subsequent product). Another option for determining whether that second product can be released involves the situation where the initial cleaning process (with the deviation) resulted in equipment that was visually clean. If the VRL (Visual Residue Limit – see Cleaning Memo of November 2020) were above the calculated L3 limit, then that may be used as support for the deviation not causing the equipment to have unacceptable levels of residues.
In both situation discussed above for “Correction”, the next step (a mandatory step if you are following CAPA) is to move to “Corrective Action”. Such corrective action to an action to change something in the cleaning process related the identified root cause such that the detected deviation that does not occur again in the future. This may involve either minor or major changes to the basic cleaning process itself, may just be additional clarifications in the written SOP instruction, may include additional routine process monitoring steps (such as a documentation of certain steps or a second person visual assessment), and will almost always some level of retraining of cleaning operators on the associated changes. These corrective actions should also include an evaluation of the effect of the changes on the validation status of the cleaning previous. There may be no additional studies needed, or there may be some studies needed up to a completely new validation protocol. As part of the “Corrective Action”, there should be a follow-up to determine that the change was actually implemented and had the intended effect (or that it didn’t have an unintended negative effect).
The third element of CAPA is “Preventive Action”. This involves other possible improvements (other than the changes made as part of “Corrective Actions”) that were identified as part of the investigation of the deviation. Ordinarily these are things that were not identified as causes of the cleaning process deviation, but based on experience or published studies could be things that improve the cleaning process such that other types of deviations do not occur in the future. They are called “preventive” because they do not address items which were clearly the root cause of the prior deviation (steps taken to address the root cause are covered in “Corrective Actions”. For example, it might be that as simple as extending the rinsing time. The rinsing time was not identified as a root cause, so that would not be addressed with a “Corrective Action”, but with a “Preventive Action”. Furthermore, as with “Corrective Actions”, any “Preventive Action” should include appropriate documentation, retraining and determination of the effect of the change on the validation status of the cleaning process. In addition, there should be some follow-up to determine that the change was actually implemented and had the intended effect (or that it didn’t have an unintended negative effect).
It should be noted that some companies may not distinguish between a deviation and a non-conformance, so some adjustments to these suggestions may be needed. Furthermore, many in the pharmaceutical industry may emphasize “Corrective Actions” and “Preventive Actions”, and talk less about “Corrections”. However, the three-part distinctions of CAPA utilized in this Cleaning Memo are consistent with the ISO 9000 definitions, which are:
Correction – Action to eliminate a detected nonconformity
Corrective action – Action to eliminate the cause of a detected nonconformity
Preventive action – Action to eliminate the cause of a potential nonconformity The idea of making “Corrections” is important to fully recognize as a critical element of a CAPA program.
Copyright © 2023 by Cleaning Validation Technologies